tbuckley/cabot-search huggingface dataset:
COVID-19 pandemic experience in patients with Hodgkin lymphoma.
Authors: Sara E. Prischak, Hatcher J. Ballard, Adam N. Duca, James M. Gerson, Daniel J Landsburg, Stefan K. Barta, Jakub Svoboda
Journal: Journal of Clinical Oncology (2022)

e19534 Background: Patients (pts) with Hodgkin lymphoma (HL) may be at an increased risk from COVID-19-related complications due to immunosuppression and common therapies with pulmonary toxicities (e.g. bleomycin, radiation). Additionally, they may experience unexpected adverse events (AEs) from the novel SARS-CoV-2 vaccines due to the intrinsic abnormalities in cellular immunity. Exploring their perspective on the COVID-19 pandemic and subjective AEs from the novel vaccines may ultimately allow providers to develop improved services based on needs of this specific population. Methods: We conducted a single-institution, questionnaire-based study in pts treated after 1/1/2015, for diagnosis of HL. Pts were identified through the electronic medical records at our institution. After signing an informed consent, pts answered 19 questions designed to reflect on their COVID-19 pandemic experience. An additional section aimed to determine the percentage of pts with a local or systemic AEs within 7 days of novel SARS-CoV-2 vaccine dose. Results: We enrolled 30 pts with median age 28.5 years (18-66); 16 (53%) were male, and 26 (87%) were on active HL therapy. With data cutoff 1/28/2022, 27 pts (90%) completed the questionnaire. A total of 8 (27%) patients had COVID-19 infection with 75% of those occurring after the vaccination. None required hospitalization and none reported residual pulmonary issues. Eighteen (67%) had a member of their household test positive for COVID-19. Most pts (67%) did not require cancellation of their appointments due to COVID-19-related issues during the pandemic. 85% of pts participated in at least 1 telehealth medical appointment and the majority (72%) were satisfied with their telehealth experience for cancer care. A total of 24 (80%) pts received the novel SARS-CoV-2 vaccines (58% had Pfizer-BioNTech BNT162b2, 38% Moderna mRNA-1273, 4% Ad26.COV2.S) and 23 pts completed the AE section of the questionnaire. The vaccines were generally well-tolerated. Six pts (26%) reported at least one grade 3 AE, but none had grade 4 local or systemic AEs. The most common AE was pain at injection site (65% after dose 1, 55% after dose 2, 69% after dose 3). AEs that occurred in over 25% of pts during any of the injections included redness/swelling/pain at the injection site, fatigue, headache, muscle pain, and fever. Of 23 eligible pts, 13 (57%) received 3 rd dose of the vaccine. No unexpected toxicities or autoimmune issues were noted by participants in this study following vaccination with a median follow up of 10 months after the 1 st vaccine dose. Conclusions: Based on responses from our study, HL pts adjusted to the challenges of the COVID-19 pandemic with minimal disruptions to their cancer care, showed positive attitudes toward telehealth, and appear without any unexpected toxicities from the novel vaccines.
Metagenomic DNA sequencing for semi-quantitative pathogen detection from urine: a prospective, laboratory-based, proof-of-concept study
Authors: Victoria A Janes, Sébastien Matamoros, Patrick Munk, Philip T L C Clausen, Sylvie M Koekkoek, Linda A M Koster, Marja E Jakobs, Bob de Wever, Caroline E Visser, Frank M Aarestrup, Ole Lund, Menno D de Jong, Patrick M M Bossuyt, Daniel R Mende, Constance Schultsz
Journal: The Lancet Microbe (2022)

Semi-quantitative bacterial culture is the reference standard to diagnose urinary tract infection, but culture is time-consuming and can be unreliable if patients are receiving antibiotics. Metagenomics could increase diagnostic accuracy and speed by sequencing the microbiota and resistome directly from urine. We aimed to compare metagenomics to culture for semi-quantitative pathogen and resistome detection from urine.In this proof-of-concept study, we prospectively included consecutive urine samples from a clinical diagnostic laboratory in Amsterdam. Urine samples were screened by DNA concentration, followed by PCR-free metagenomic sequencing of randomly selected samples with a high concentration of DNA (culture positive and negative). A diagnostic index was calculated as the product of DNA concentration and fraction of pathogen reads. We compared results with semi-quantitative culture using area under the receiver operating characteristic curve (AUROC) analyses. We used ResFinder and PointFinder for resistance gene detection and compared results to phenotypic antimicrobial susceptibility testing for six antibiotics commonly used for urinary tract infection treatment: nitrofurantoin, ciprofloxacin, fosfomycin, cotrimoxazole, ceftazidime, and ceftriaxone.We screened 529 urine samples of which 86 were sequenced (43 culture positive and 43 culture negative). The AUROC of the DNA concentration-based screening was 0·85 (95% CI 0·81-0·89). At a cutoff value of 6·0 ng/mL, culture positivity was ruled out with a negative predictive value of 91% (95% CI 87-93; 26 of 297 samples), reducing the number of samples requiring sequencing by 56% (297 of 529 samples). The AUROC of the diagnostic index was 0·87 (95% CI 0·79-0·95). A diagnostic index cutoff value of 17·2 yielded a positive predictive value of 93% (95% CI 85-97) and a negative predictive value of 69% (55-80), correcting for a culture-positive prevalence of 66%. Gram-positive pathogens explained eight (89%) of the nine false-negative metagenomic test results. Agreement of phenotypic and genotypic antimicrobial susceptibility testing varied between 71% (22 of 31 samples) and 100% (six of six samples), depending on the antibiotic tested.This study provides proof-of-concept of metagenomic semi-quantitative pathogen and resistome detection for the diagnosis of urinary tract infection. The findings warrant prospective clinical validation of the value of this approach in informing patient management and care.EU Horizon 2020 Research and Innovation Programme.
Need of pretreatment support of breast cancer patient caregivers compared to patients.
Authors: Terri Kim, Dasom Lee, Hajin Lee, Chan-Young Ock, Hyungkook Yang, Ki Hwan Kim, Jane Shin, Anthony S Paek, Jamie Eunsu Park, Yerin Lee, Hyejin Son, Hongseok Choi, Hyemin Shim
Journal: Journal of Clinical Oncology (2022)

e24001 Background: Through this research, Lunit is seeking to understand how the needs of breast cancer patient caregivers differ from those of patients. Moreover, we seek to gain insights into the potential impact of fulfilling such needs for caregivers through remote nurse support that can provide evidence-based information. Methods: We asked 330 breast cancer patients and 53 caregivers to participate in an online survey in Korea from 10/2021- 11/2021 to understand various needs throughout their cancer journey. Eight breast cancer patients and caregivers asked 25 questions through a remote nurse support model. Interactions took place either via phone or text, starting 12/20/2021 and is ongoing. The answers to asked questions were drafted by nurses and reviewed by a team of medical doctors to ensure delivery of clinically sound information. Results: While the top areas needing support during the entire cancer journey (prior, during, post treatment) were generally consistent for both caregivers and patients, caregivers showed a pronounced need for support that would help make treatment decisions specifically during the pre-treatment phase. (See table below) This difference was also reflected in the distribution of questions asked during the remote nurse support service. Caregivers asked questions about treatment options that required significant clinical knowledge to answer. In contrast, questions from patients were concentrated in understanding their cancer and in seeking dietary recommendations to keep their cancer at bay. Conclusions: We observed early evidence that improving access to evidence-based information for caregivers will not only contribute to improved outcomes for the patient but also have a positive impact on the well-being of caregivers, which again in turn is expected to have a positive impact on the patient.[Table: see text]
Connective tissue growth factor expression maintains the epithelial phenotype of ovarian cancer in early epithelial to mesenchymal transition.
Authors: Harry Ramos, Sandra Galoforo, Yuan You, Ira Seth Winer, Gil Mor, Ayesha Alvero, Radhika Gogoi
Journal: Journal of Clinical Oncology (2022)

e17544 Background: Epithelial to Mesenchymal Transition (EMT) is essential to the process of metastasis in ovarian cancer (OC). Early expressions of proteins and pathways during EMT essential for understanding mechanism and potential therapeutic targets in OC. The aim of our study is to evaluate the role and mechanism of Connective Tissue Growth Factor (CTGF) in OC. Methods: R182 and R2615 are well-characterized epithelial OC cell lines. CTGF expression +/- Transforming Growth Factor -b (TGF-b) was determined via Western blot. R182 and R2615 CTGF knock out (KO) were derived utilizing a Cas9/CRISPR-Cas9 lentivirus plasmid vector and confirmed via PCR. Anoikis resistance and invasion assays were performed to characterize phenotypes of R182 and R2615 wild type (WT) and KO cells. For anoikis resistance, cells were plated in triplicate in an ultra-low adhesive (ULA) cell plate Promega CellTiter assay which measured cell viability quantified by absorbance at 450 nm at 0, 24, 48, and 72 hrs. For invasion assay, 3000 cells were suspended in 50% reduced growth factor Basement Membrane Extract. Human recombinant CTGF was added at 50 and 100 ng/mL concentrations. Cells were plated in tissue culture plate and placed in Cytation 5/Biospa and imaged at 4-hour interval for up to 6 days. Western blot evaluated expression of mesenchymal markers. Chemo-sensitivity was measured by half maximal inhibitory concentration (IC50) for Cisplatin between the WT and KO cells. RNA sequence analysis was performed for both R182 WT and KO cells and analyzed utilizing iPathway Guide. Results: CTGF is constitutively expressed in R182 and R2615 OC cells line as early as 6 hrs of culture and after 30 min of TGF-b treatment. Loss of CTGF promoted anoikis resistance. At 72 hr, R182 CTGF WT cells displayed 75% viability while R182 KO only have 10% viability. Further, we demonstrated that loss of CTGF increases invasion. Administration of exogeneous CTGF in KO cells suppresses invasion in a dose dependent manner demonstrated. Along with epithelial markers CK-18 and beta-catenin, the KO cells expressed the mesenchymal marker SNAIL. No difference in chemo-sensitivity to Cisplatin was seen between WT and KO in either cell line. RNA sequence analysis identified 1106 out of 14054 differentially expressed genes between the WT and KO cells. PI3KAkt, cell adhesion molecules and ECM receptor interaction were pathway that were most significantly regulated. Conclusions: CTGF expression maintains the epithelial phenotype of OC cells during EMT. Loss of CTGF allows anoikis resistance and invasion which are vital characteristics in the metastatic nature of OC. We suggest that loss of CTGF expression in OC cells could be a biomarker for more aggressive OC.
Pregnancy and Spontaneous Coronary Artery Dissection: Lessons From Survivors and Nonsurvivors
Authors: Nathan Chan, Diluka Premawardhana, Abtehale Al-Hussaini, Alice Wood, Vasiliki Bountziouka, Deevia Kotecha, Eva Swahn, Henning Palmefors, Christos Pagonis, Sofia Sederholm Lawesson, Jacek Kądziela, Marcos Garcia-Guimarães, Fernando Alfonso, Javier Escaned, Fernando Macaya, Melisa Santás, Enrico Cerrato, Angela H.E.M. Maas, Ota Hlinomaz, Nigussie Bogale, Bernardo Cortese, Mavis Cheng, Aidan Bolger, Shazia T. Hussain, Nilesh J. Samani, Marian Knight, Matthew Cauldwell, David Adlam
Journal: Circulation (2022)
Is recent FDA guidance on HRQoL clinical significance a barrier to clinician/patient treatment risk/benefit discussions: An example using EORTC scale endpoints in a randomized, phase 3 trial.
Authors: Lauren Podger, Shauna McManus, Charles Iaconangelo, Daniel Serrano
Journal: Journal of Clinical Oncology (2022)

e21066 Background: Recent FDA guidance on clinical significance thresholds (CSTs) may adversely affect the evaluation of EORTC endpoints, thereby altering clinician/patient discussions about treatment (Tx) risk/benefit for emerging Tx. Specifically, FDA now rejects historic CSTs for EORTC measures (e.g., Osoba, 1998 10-point change). FDA’s guidance implies that EORTC function/symptom CSTs should be ±33.33 1 ; in addition, Tx arms must separate at the CST. Few, if any, EORTC domains are likely to achieve CSTs 3 times those of Osoba (1998). Holding health-related quality of life (HRQoL) endpoints to this standard may limit detection of clinically meaningful patient-centric Tx benefits &amp; clinician/patients dialogue about HRQoL for emerging cancer Tx. The NCI-conducted Sunitinib trial data (NCT00693992), obtained through Project DataSphere, was used to generate revised deterioration thresholds for EORTC scales under an anchor-based meaningful change approach. This this Phase 3 trial met it’s primary PFS endpoint. Evidence from this research highlights the potential implications of the FDAs position on COA-based CSTs. Methods: The Sunitinib trial was a randomized, phase 3 study comparing the efficacy &amp; safety of Sunitinib versus placebo as a maintenance therapy in non-progressing patients following chemotherapy in advanced non-small cell lung cancer. Symptoms &amp; HRQoL were measured by EORTC LC13. The analysis population consisted of 107 patients in the HRQoL substudy completing the QLQ-C30 Global Health/QoL scale (GHS). The GHS was used to categorize patients into: no change (0 pt. change), deterioration (≤-1 pt. change) &amp; improvement (≥1 pt. change). Deterioration thresholds were estimated as the mean LC13 scale change-scores &amp; visualized with empirical cumulative distribution functions (eCDFs). Results: See Table. Within this population, interpretable mean deterioration CSTs were found Dyspnea, Diarrhea, and Nausea/Vomiting. At these CSTs, Tx arms separated in eCDFs except for Dyspnea. However, while Dyspnea &amp; Diarrhea CSTs exceeded Osoba’s CSTs, none met the FDA criterion of + 33.33 points change. Conclusions: The LC13 scores had interpretable CSTs; evidence suggests FDA’s CST criterion may be unachievable for EORTC scales &amp; may thereby affect HRQoL endpoints. This research was limited by the use of the GHS as an anchor variable rather than a PGIS. The main risk is that FDA’s CST criterion may limit the characterization of truly meaningful Tx benefits for patients &amp; clinician communication with patients about HRQoL for emerging Tx. Clinical trial information: NCT00693992. [Table: see text]
Molecular characterization to delineate the clonal evolution of primary prostate cancer with synchronous lymph node metastasis
Authors: U. Singhal, S. Nallandhighal, J.J. Tosoian, T. Pham, R. Kareem, K.R. Plouffe, T.M. Morgan, R. Luciano, S.F. Shariat, N. Finocchio, L. D'Ambrosio, C. Doglioni, S.A. Tomlins, A. Briganti, G.S. Palapattu, A.M. Udager, S.S. Salami
Journal: European Urology (2022)
ATRT-03. Adapted Treatment Protocol: Synchronous Atypical Teratoid/Rhabdoid CNS Tumor and Extra CNS Disease
Authors: Nicole Jackson, Marleni Torres, Eva Glenn Lecea, Candelaria O’Farrell, Ziad Khatib, Ossama Maher
Journal: Neuro-Oncology (2022)

Abstract Atypical teratoid/rhabdoid tumors (AT/RTs) of the central nervous system (CNS) are rare, aggressive, early childhood tumors with unfavorable prognosis. There have been 31 cases reported of children with AT/RT of the CNS and extra CNS primary tumors. In addition to its aggressive tendencies, malignant rhabdoid tumors (MRTs) of the kidney have also shown a common genetic abnormality-inactivating mutation of SMARC B1/INI-gene. We report a 22-month-old male who presented at 15 months of age with metastatic AT/RT of the posterior fossa and synchronous malignant rhabdoid tumor of the left kidney. MRI of the brain demonstrated a midline posterior fossa mass and left renal mass was noted incidentally on imaging of spine. Pathology was consistent with MRT of the kidney and pathogenic variant was found in the tumor sample, specifically SMARCB1 homozygous/biallelic deletion. Patient underwent a subtotal resection of the posterior fossa tumor and subsequent radical resection of the mass on kidney rhabdoid tumor. He was treated as per ACNS033 protocol with 2 cycles of induction with high-dose methotrexate followed by vincristine, cyclophosphamide, cisplatin, and etoposide with complete response followed by three tandem stem cell transplants with thiotepa and carboplatin for which he has been tolerating and responding favorably. Focal radiation therapy to the brain and flank area is planned at end of therapy. In a large series of synchronous AT/RTs reported in 2017 only 3 of the 31 patients were considered long-term survivors. All received a combination of high dose intrathecal or intravenous chemotherapy, total resection of at least one of the tumors, focal radiation, and autologous peripheral blood stem cell transplant. We demonstrated a case with a favorable response with our treatment. Treatment continues to be challenging given the tumor’s rarity and mortality as there are no standardized protocols or randomized controlled trials.
Evaluation of the learning curve for Thulium laser enucleation of the prostate using multiple outcome measures
Authors: L. Berti, M. Maltagliati, U. Besana, C. Buizza, J.B. Roche, B. Rocco, S. Micali, M.C. Sighinolfi, A. Pacchetti, G. Bozzini
Journal: European Urology (2022)
GCT-02. Imaging response assessment for Central Nervous System Germ Cell Tumours: consensus recommendations from the European Society for Paediatric Oncology Brain Tumour Group (SIOPE-BTG) and North American Children’s Oncology Group (COG)
Authors: Giovanni Morana, Dennis Shaw, Shannon MacDonald, Claire Alapetite, Thankamma Ajithkumar, Aashim Bhatia, Hervé Brisse, Camilo Jaimes, Thomas Czech, Girish Dhall, Jason Fangusaro, Cecile Faure-Conter, Maryam Fouladi, Darren Hargrave, Julie Harreld, Dipayan Mitra, James Nicholson, Mark Souweidane, Beate Timmermann, Gabriele Calaminus, Ute Bartels, Brigitte Bison, Matthew Murray
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Central nervous system (CNS) germ cell tumours (GCT) comprise a heterogeneous and relatively rare group of neoplasms. Improving the ability to conduct international clinical trials for CNS GCT requires use of homogeneous, common objective disease assessments and standardised response criteria. Currently, different criteria are employed between European and North American protocols for assessing radiological disease response. METHODS: An international working group of the European Society for Paediatric Oncology (SIOPE) Brain Tumour Group (BTG) and North American Children’s Oncology Group (COG) was therefore established to develop consensus recommendations for imaging response assessment for CNS GCT. The working group first reviewed existing literature and current practices and identified major challenges regarding imaging assessment. RESULTS: New clinical imaging standards were defined for the most common sites of intracranial GCT disease (suprasellar/pineal/bifocal), as well as for definition of loco-regional extension. In particular, clear standards were highlighted for definition of partial response (PR) and complete response (CR) to induction chemotherapy at different sites. Furthermore, growing teratoma syndrome (GTS) was clearly defined [apparent radiological increase in non-germinomatous GCT (NGGCT) size during induction chemotherapy despite normalising/normalised AFP/HCG markers – requiring surgery], to avoid such potential cases being classified as progressive disease (PD). CONCLUSION: This consensus will allow more consistent prospective neuroradiological evaluation of response to therapy for patients with CNS GCT and facilitate direct comparison of treatment outcomes across international studies. Ultimately, it may allow international trials to be developed and undertaken across a larger group of collaborating nations, which will be essential to answer many of the remaining questions for this rare but diverse group of tumours.
Extracellular stiffness as a determinant of cardiac dysfunction in duchenne muscular distrophy: a study on human iPSC derived cardiomyocytes
Authors: L Giammarino, L Santini, C Palandri, M Musumeci, M Langione, JM Pioner, C Ferrantini, R Coppini, E Cerbai, C Poggesi
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Fondazione Intesa San Paolo Introduction Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive degeneration of striated muscles; in addition to skeletal muscle impairment, DMD is also characterized by progressive myocardial disfunction. The low translational value of animal models and the low availability of human samples make DMD hard to investigate; induced pluripotent stem cells (iPSCs) represent a novel tool to model this disease, preserving the genetic heritage of the patient, including the pathogenic mutation causing dystrophy. Aim Our aim is to characterize cardiomyocytes differentiated from iPSCs (iPSC-CMs) derived from healthy donors (CTRL) and DMD patients, to identify the pathophysiological mechanisms of DMD-related cardiomyopathy. Materials and Methods Cardiomyocytes are differentiated from IPSCs obtained by reprogramming isolated mononucleated blood cells from healthy donors and DMD patients. IPSC-CMs are cultured until day 60, 75 or 90 post-differentiation after plating on nanostructured substrates with two different stiffness levels: PEG-substrates, with lower rigidity, mimicking healthy extracellular tissue, and DEG-substrates, with greater rigidity, that mimic the presence of myocardial fibrosis. Through imaging techniques, we evaluated calcium handling and action potentials (AP) on DMD and CTRL iPSC-CMs by using specific fluorescent dyes for Ca2+ (CAL630) and membrane voltage (Fluovolt). Cells were stimulated at different pacing rates. Results The calcium transient amplitude of CTRL-iPSC-CMs became larger during maturation. This adaptation did not occur in DMD lines, showing a deficit calcium release due to poor maturation of the sarcoplasmic reticulum (SR). AP duration was shorter in the DMD line at d75 but at d90 we observed no differences when compared with the CTRL line. CTRL iPSC-CMs showed a marked ability to adapt to different substrate stiffnesses. Indeed, the calcium transient amplitude was larger and its kinetics faster when cells were grown on the rigid DEG substrates rather than on PEG plates. In the DMD line, however, no differences were observed between the substrates. Conclusions Our results highlight a scarce ability of DMD iPSC-CM to adapt to different substrate stiffness, resulting in mechanical and electrical impairment, especially in the presence of stiffer substrates. This might explain why cardiac impairment is usually absent in the early stages of DMD, when cardiac structural changes are still absent. However, the electrophysiological and mechanical impairment of DMD hearts may precipitate rapidly when extracellular stiffness starts to increase due to development of cardiac fibrosis.